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The effect of antihyperglycemic drugs on prevention of the diabetes via mTORC1 signal

Research Project

Project/Area Number 16K09803
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Endocrinology
Research InstitutionKobe University

Principal Investigator

Maki Koyanagi-Kimura  神戸大学, 医学部附属病院, 特定助教 (40623690)

Research Collaborator Kannno Ayumi  
Asahara Shun-ichiro  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsmTORC1活性 / 膵β細胞量 / mTORC1 / DPP-4阻害薬 / 糖尿病
Outline of Final Research Achievements

The preservation of pancreatic βcell mass is an essential factior in the onset and development of type 2 diabetes mellitus.In this study, we aimed at indentification of antihyperglycemic drugs on prevention of the diabetes via mTORC1 signal. We administered βTSC2-/-mice to DPP-4 inhibitors, SGLT2 inhibitors to db/db mice. DPP-4 inhibitors prevented decrease in insulin signaling. SGLT2 inhibitors preserved pancreatic beta cell mass more effectively if administartion is earlier.
Maintenance of GCN2-deficient mice on a high-fat diet results in a loss of pancreatic beta cell mass. Our data suggest that GCN2 senses amino acid deficiency in beta cells and limits signaling by mechanistic target of rapamycin complex 1 to prevent beta cell failure during the consumption of a high-fat diet. The present results provide an insight into the genetic predisposition to T2DM in non-obese Asian populations, and they may inform a strategy for intervention in those with the risk allele for this SNP.

Academic Significance and Societal Importance of the Research Achievements

DPP-4阻害薬はインスリンシグナルの減弱化の改善を介して膵β細胞保護に寄与すると考えられた。早期SGLT2投与db/dbマウスではAgr2、Tff2、Gkn3遺伝子発現上昇により膵β細胞量保持のlegacy effectに寄与している可能性が考えられた。また、GCN2は高脂肪食負荷による過栄養の際、プロインスリンmRNAの翻訳が亢進すると活性化され、SESN2の発現低下によるmTORC1活性の亢進を介して膵β細胞量維持が破綻する可能性が示唆された。すなわち本研究は、2 型糖尿病候補遺伝子GCN2のSNPを有する患者が過食による膵β細胞不全を未然に防ぎうる手段を講じることに役立つと考えられた。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (14 results)

All 2019 2018 2017 2016

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (10 results)

  • [Journal Article] Early administration of dapagliflozin preserves pancreatic β-cell mass through a legacy effect in a mouse model of type 2 diabetes2019

    • Author(s)
      Kanno A, Asahara SI, Kawamura M, Furubayashi A, Tsuchiya S, Suzuki E, Takai T, Koyanagi-Kimura M, Matsuda T, Okada Y, Ogawa W, Kido Y.
    • Journal Title

      J Diabetes Invest.

      Volume: 10 Issue: 3 Pages: 577-590

    • DOI

      10.1111/jdi.12945

    • NAID

      120006645694

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Docosahexaenoic acid reduces palmitic acid-induced endoplasmic reticulum stress in pancreatic β cells2018

    • Author(s)
      Suzuki E, Matsuda T, Kawamoto T, Takahashi H, Mieda Y, Matsuura Y, Takai T, Kanno A, Kimura-Koyanagi M, Asahara S.-i, Inoue H, Ogawa W, Kido Y
    • Journal Title

      Kobe J.Med.Sci.

      Volume: 64

    • NAID

      120006523798

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Casein kinase 2 phosphorylates and stabilizes C/EBPβ in pancreatic β cells.2018

    • Author(s)
      Takai T, Matsuda T, Matsuura Y, Inoue K, Suzuki E, Kanno A, Kimura-Koyanagi M, Asahara SI, Hatano N, Ogawa W, Kido Y.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 497 Issue: 1 Pages: 451-456

    • DOI

      10.1016/j.bbrc.2018.02.108

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells.2017

    • Author(s)
      Kawada Y, Asahara SI, Sugiura Y, Sato A, Furubayashi A, Kawamura M, Bartolome A, Terashi-Suzuki E, Takai T, Kanno A, Koyanagi-Kimura M, Matsuda T, Hashimoto N, Kido Y.
    • Journal Title

      PLoS ONE

      Volume: 12 Issue: 9 Pages: e0184435-e0184435

    • DOI

      10.1371/journal.pone.0184435

    • NAID

      120006353753

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 2型糖尿病感受性遺伝子GCN2はSestrin2を介して膵β細胞量の調節に関与する2018

    • Author(s)
      古林鮎子
    • Organizer
      第91回日本内分泌学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] グルタミングルタミン酸シグナルによるインスリン分泌増強機構の解明2018

    • Author(s)
      韓 桂栄
    • Organizer
      第61回日本糖尿病学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ヒトiPS細胞を用いた膵内分泌細胞への分化誘導2018

    • Author(s)
      山田瑞姫
    • Organizer
      第61回日本糖尿病学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 膵β細胞の小胞体ストレス誘導性アポトーシスにおけるCK2βの役割2017

    • Author(s)
      高井智子、松田友和、井上佳歩、松浦有希、鈴木江美、神野歩、木村真希、淺原俊一郎、小川渉、木戸良明
    • Organizer
      第60回日本糖尿病学会年次学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 脂肪酸が膵β細胞の小胞体に及ぼす影響2017

    • Author(s)
      鈴木江美、松田友和、川本剛士、松浦有希、高井智子、神野歩、木村真希、淺原俊一郎、小川渉、木戸良明
    • Organizer
      第60回日本糖尿病学会年次学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] ヒトiPS細胞を用いた2型糖尿病発症機序の解明2017

    • Author(s)
      下野名奈子、淺原俊一郎、原瑞季、田中孝一、松田友和、木村真希、神野歩、高井智子、鈴木江美、青井貴之、木戸良明
    • Organizer
      第60回日本糖尿病学会年次学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 膵β細胞の小胞体ストレス誘導性アポトーシスにおけるCK2βの役割2017

    • Author(s)
      井上佳歩、高井智子、松田友和、鈴木江美、神野歩、木村真希、淺原俊一郎、木戸良明
    • Organizer
      第40回分子生物学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] 高脂肪食負荷GCN2欠損マウスの膵島におけるmTORC1シグナル調節機構の解明2017

    • Author(s)
      古林鮎子、神野歩、増田勝久、吉富理紗、木村真希、松田友和、淺原俊一郎、木戸良明
    • Organizer
      第40回分子生物学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] ヒトiPS細胞を用いた膵内分泌細胞への分化誘導法の確立2017

    • Author(s)
      山田瑞姫、淺原俊一郎、下野名奈子、田中孝一、松田友和、木村真希、神野歩、高井智子、鈴木江美、青井貴之、木戸良明
    • Organizer
      第40回分子生物学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] 2型糖尿病感受性遺伝子GCN2は膵β細胞量の調節に関与する2016

    • Author(s)
      神野歩
    • Organizer
      第89回日本内分泌学会学術集会
    • Place of Presentation
      京都
    • Year and Date
      2016-04-21
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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